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  Structure-toxicity relationships in the amatoxin series. Structural variations of side chain 3 and inhibition of RNA polymerase II

Zanotti, G., Petersen, G., & Wieland, T. (1992). Structure-toxicity relationships in the amatoxin series. Structural variations of side chain 3 and inhibition of RNA polymerase II. International journal of peptide and protein research, 40(6), 551-558. doi:10.1111/j.1399-3011.1992.tb00440.x.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-1769-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-68D3-B
Genre: Journal Article

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IntJPeptProtRes_40_1992_551.pdf (Any fulltext), 5MB
 
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 Creators:
Zanotti, Giancarlo, Author
Petersen, Gabriele, Author
Wieland, Theodor1, Author              
Affiliations:
1Max Planck Institute for Medical Research, Max Planck Society, ou_1125545              

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 Abstract: The amatoxins, highly toxic components of death cap Amanita mushrooms, bind strongly to RNA polymerase II (or B) in cell nuclei thus preventing the transcription of DNAs to hn-RNAs (Pre-mRNAs), the precursors of messenger RNAs. Three of the binding sites of the bicyclic octapeptides have been identified: an isoleucine side chain in position 6, a trans-4-hydroxyl group at proline in position 2 and a hydroxylated L-isoleucine side chain in position 3. No information exists about the stereochemical conditions at the beta-C-atom (C-atom 3) of this side chain. We have now synthesized the diastereomeric S-deoxo-amaninamides (Fig. 1) containing, in position 3, L-allo-isoleucine (analog 1), (2S, 3R)-2-amino-4-hydroxy-3-methyl butyric acid (analog 2), the diastereomer (2S, 3S)-2-amino-4-hydroxy-3-methylbutyric acid (analog 3) and D-isoleucine (analog 4). In the last synthesis, besides the "normal" bicyclic octapeptide 4, an isomeric Iso-4 was formed. The affinities for Drosophila RNA polymerase II were 100 times weaker as compared to gamma-amanitin for 1, 10 times weaker for 2, 200 times weaker for 3, 100 times weaker for 4, and more than 1000 times weaker for Iso-4. The results point to the importance of a methyl group in (R)-configuration at the beta-C atom of side chain 3.

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Language(s): eng - English
 Dates: 1992-02-031992-05-161992-12-01
 Publication Status: Published in print
 Pages: 8
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 Rev. Type: Peer
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Title: International journal of peptide and protein research
Source Genre: Journal
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Publ. Info: Copenhagen : Munksgaard
Pages: - Volume / Issue: 40 (6) Sequence Number: - Start / End Page: 551 - 558 Identifier: ISSN: 0367-8377
ISSN: 0300-9769